PROJECT: JTC2023 - Resilience: CLEVER

Major depressive disorders (MDD) are common psychiatric illnesses with insufficient early detection and long-term assessment to prevent suicidal behaviors. We hypothesize that regional changes of brain activity linked to MDD reflect the utilization of distinct fuel sources for its metabolism. The assumption is that MDD patients rely more on fat than carbohydrates to supply energy demands for the brain contrary to healthy controls that rely more on carbohydrates than fat. We ask if resilience can be promoted by rebalancing fat and carbohydrate utilization in the brain? The project is designed as reverse translation from patients to animal models, by exploiting the biobank of a multicenter study comprising 889 MDD patients comparing an early medication change strategy with treatment as usual. The primary objective is to discover genes/pathways truly relevant for individuals that are more vulnerable to MDD and insufficient treatment response. The secondary objective is to exploit the candidate genes as proof-of-concept to restore fuel utilization towards more carbohydrates and less lipids in the brain of preclinical animal models of MDD. We propose an innovative approach linking the epigenetic makeup to the metabolism that will lead to better stratification of MDD diagnosis, monitoring, and treatment. The project will provide conceptual advance in normal and dysfunctional brain/body metabolism, paving the way for making a difference to patients and/or care givers.